Scientia Pharmaceutica最新文献

{"title":"In Vitro and In Silico Screening Analysis of Artabotrys sumatranus Leaf and Twig Extracts for α-Glucosidase Inhibition Activity and Its Relationship with Antioxidant Activity","authors":"D. Rosa, B. Elya, M. Hanafi, A. Khatib, M. I. Surya","doi":"10.3390/scipharm91010002","DOIUrl":"https://doi.org/10.3390/scipharm91010002","url":null,"abstract":"Artabotrys sumatranus is one of the Artabotrys species, which lives in Sumatera, Java, and Borneo in Indonesia. No research has been found related to its activity. The objective of this study was to explore the potential of A. sumatranus leaf and twig extracts as the source of an anti-diabetic agent through the α-glucosidase inhibition mechanism, as well as the relationship between the antioxidant and the α-glucosidase inhibition activities in these extracts. Ethanol extracts from leaf and twig A. sumatranus were subjected to several assays: total phenolic content, total flavonoid content, antioxidant activity using DPPH (2,2-diphenyl-1-picrylhydrazyl), radical scavenging activity, and FRAP (ferric reducing antioxidant power) analysis, as well as α-glucosidase inhibition. Later, GC-MS (gas chromatography-mass spectrometer) and LC-MS/MS (liquid chromatography-mass spectrometer/mass spectrometer) analysis were conducted to identify the compounds inside the extracts. The identified compounds were tested for potential α-glucosidase inhibition activity using a molecular docking simulation. As a result, the A. sumatranus leaf extract showed more potential than the twig extract as α-glucosidase inhibitor and antioxidant agent. In addition, from the comparison between the measured quantities, it can be deduced that most of the α-glucosidase active compounds in the A. sumatranus are also antioxidant agents. Several active compounds with a high affinity to α-glucosidase inhibition were identified using the molecular docking simulation. It was concluded that A. sumatranus twig and leaf extracts seem to be potential sources of α-glucosidase inhibitors.","PeriodicalId":21601,"journal":{"name":"Scientia Pharmaceutica","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47564381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral Bioavailability Enhancement of Vancomycin Hydrochloride with Cationic Nanocarrier (Leciplex): Optimization, In Vitro, Ex Vivo, and In Vivo Studies","authors":"Menna M. Abdellatif, S. M. Ahmed, M. EL-NABARAWI, M. Teaima","doi":"10.3390/scipharm91010001","DOIUrl":"https://doi.org/10.3390/scipharm91010001","url":null,"abstract":"To explore the performance of the cationic nanocarrier leciplex (LPX) in escalating the oral bioavailability of vancomycin hydrochloride (VAN) by promoting its intestinal permeability. With the aid of a D-optimal design, the effect of numerous factors, including lipid molar ratio, cationic surfactant molar ratio, cationic surfactant type, and lipid type, on LPX characteristics, including entrapment efficacy (EE%), particle size (P.S.), polydispersity index (P.I.), zeta potential value (Z.P.), and steady-state flux (Jss) were assessed. The optimized formula was further evaluated in terms of morphology, ex vivo permeation, stability, cytotoxicity, and in vivo pharmacokinetic study. The optimized formula was spherical-shaped with an E.E. of 85.2 ± 0.95%, a P.S. of 52.74 ± 0.91 nm, a P.I. of 0.21 ± 0.02, a Z.P. of + 60.8 ± 1.75 mV, and a Jss of 175.03 ± 1.68 µg/cm2/hr. Furthermore, the formula increased the intestinal permeability of VAN by 2.3-fold compared to the drug solution. Additionally, the formula was stable, revealed good mucoadhesive properties, and was well tolerated for oral administration. The in vivo pharmacokinetic study demonstrated that the VAN Cmax increased by 2.99-folds and AUC0-12 by 3.41-folds compared to the drug solution. These outcomes proved the potentiality of LPX in increasing the oral bioavailability of poorly absorbed drugs.","PeriodicalId":21601,"journal":{"name":"Scientia Pharmaceutica","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45842224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Aqueous Extracts of Quercus resinosa on the Mechanical Behavior of Bigels","authors":"J. Gallegos‐Infante, María del Pilar Galindo-Galindo, M. Moreno‐Jiménez, N. Rocha‐Guzmán, R. González-Laredo","doi":"10.3390/scipharm90040073","DOIUrl":"https://doi.org/10.3390/scipharm90040073","url":null,"abstract":"Quercus resinosa leaves are rich in polyphenol compounds, however, they are unstable to several chemical and physical factors that limit their activity. Several methods have been developed to solve such problems, among which bigels can be mentioned and obtained using hydrogels and oleogels. The mechanical characterization of this type of materials is by using rheological methods. Although the use of these methods is well documented, the Carreau-Yasuda model has been little used to evaluate the effect of polyphenols on the mechanical behavior of bigels. Therefore, bigels were obtained from hydrogels (guar gum/xanthan gum, 0.5/0.5% w/v) and oleogels (sesame oil/sorbitan monostearate 10% w/w). Micrographs, linear viscoelasticity range, frequency sweep, and single shear tests were performed. The data were analyzed using ANOVA and Tukey test (p < 0.05); micrographs showed linear relationship between polyphenols concentration and droplet size. Liquid fraction of bigels showed a pseudoplastic behavior, while the parameters of Carreau-Yasuda model showed that the highest value of the complex viscosity at zero shear was at the lowest concentration of extract; the relaxation time presented the lowest value at higher concentrations of extracts. These results indicate that the presence of polyphenols modifyes the mechanical behavior of bigels.","PeriodicalId":21601,"journal":{"name":"Scientia Pharmaceutica","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41696676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uptake of Cationic PAMAM-PLGA Nanoparticles by the Nasal Mucosa","authors":"Mohammed A. Albarki, M. Donovan","doi":"10.3390/scipharm90040072","DOIUrl":"https://doi.org/10.3390/scipharm90040072","url":null,"abstract":"Nanoparticles provide promising advantages in advanced delivery systems for enhanced drug delivery and targeting. The use of a biodegradable polymer such as PLGA (poly lactic-co-glycolic acid) promotes improved nanoparticle safety and, to some extent, provides the ability to modify nanoparticle surface properties. This study compared the effect of altering the surface charge on the translocation of PLGA nanoparticles across excised nasal mucosal tissues. Nanoparticles (average diameter of 60–100 nm) loaded with Nile Red (lipophilic fluorescent dye) were fabricated using a nanoprecipitation method. The effects of nanoparticle surface charge were investigated by comparing the transfer of untreated nanoparticles (negatively charged) and positively charged PLGA nanoparticles, which were modified using PAMAM dendrimer (polyamidoamine, 5th generation). All nanoparticles were able to be transferred in measurable quantities into both nasal respiratory and olfactory mucosae within 30 min. The total nanoparticle uptake was less than 5% of the nanoparticle mass exposed to the tissue surface. The cationic nanoparticles showed a significantly lower transfer into the mucosal tissues where the amount of nanoparticles transferred was 1.8–4-fold lower compared to the untreated negatively charged nanoparticles. The modification of the nanoparticle surface charge can alter the nanoparticle interaction with the nasal epithelial surface, which can result in decreasing the nanoparticle transfer into the nasal mucosa.","PeriodicalId":21601,"journal":{"name":"Scientia Pharmaceutica","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42409821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancement of the Solubility and Dissolution Rate of Telmisartan by Surface Solid Dispersions Employing Superdisintegrants, Hydrophilic Polymers and Combined Carriers","authors":"Reem A. Aldeeb, M. El-Miligi, M. EL-NABARAWI, Randa Tag, Hany M. S. Amin, A. A. Taha","doi":"10.3390/scipharm90040071","DOIUrl":"https://doi.org/10.3390/scipharm90040071","url":null,"abstract":"Telmisartan (Tel) is a potent antihypertensive drug with a very poor aqueous solubility, especially in pH ranging from 3 to 9 (i.e., biological fluids) that results in poor bioavailability. Our aim was to improve Tel solubility and dissolution rates without the need for expensive multistep procedures, and without inclusion of alkalinizers. This study adopted the use of surface solid dispersions (SSDs) employing superdisintegrants, hydrophilic polymers and combined carriers including a superdisintegrant with a hydrophilic polymer. Tel-SSDs were formulated using thesolvent evaporation method. Compatibility between Tel and different carriers was examined via FT-IR. Tel-SSDs were evaluated optically and thermally to reveal a complete loss of the crystalline nature of the drug. Both drug content and percentage yield were calculated to judge the efficiency of the preparation technique used. Saturation, aqueous solubility, and dissolutions rates were determined. Dissolution profiles were studied using model dependent and independent approaches and were subjected to the pair-wise procedure using the DDsolver software program. Effect of aging was studied by comparing the drug content and dissolution profiles of freshly prepared SSDs with aged samples. All Tel-SSDs showed acceptable physical properties. Tel-SSDs showed pertinent enhancement related to the carrier used. Combined surface solid dispersions employing superdisintegrant croscarmellose sodium with either hydrophilic polymer PEG 4000 or Poloxamer 407 gave remarkable enhancement in solubility and dissolution rates of Tel where more than 90% of the drug was released within 20 min. The effect of aging results proved a non-significant difference in the drug content and dissolution profiles between fresh and aged samples. Formulation of Tel SSDs using combined carriers proved to be effective in enhancing the aqueous solubility and dissolution rates of Tel, as well as showing good stability upon aging.","PeriodicalId":21601,"journal":{"name":"Scientia Pharmaceutica","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46422195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-Sporotrichotic Activity, Lambert-W Inhibition Kinetics and 3D Structural Characterization of Sporothrix schenckii Catalase as Target of Glucosinolates from Moringa oleifera","authors":"E. Sierra-Campos, M. Valdez-Solana, E. Ruiz-Baca, Erica K. Ventura-García, Claudia Avitia-Domínguez, M. Aguilera-Ortíz, A. Téllez-Valencia","doi":"10.3390/scipharm90040070","DOIUrl":"https://doi.org/10.3390/scipharm90040070","url":null,"abstract":"Most human fungal infections exhibit significant defensive oxidative stress responses, which contribute to their pathogenicity. An important component of these reactions is the activation of catalase for detoxification. To discover new antifungal chemicals, the antifungal activity of methanol extracts of Moringa oleifera from two commercial products (Akuanandi and Mas Lait) was investigated. The methanolic extracts’ activity against Sporothrix schenckii was determined using an assay for minimum inhibitory concentration (MIC) and minimum lethal concentration (MLC). The MIC concentrations varied between 0.5 μg/mL and 8 μg/mL. Akuanandi extract had the lowest MIC (0.5 μg/mL) and MLC (1 μg/mL) values. M. oleifera methanolic extracts were tested for catalase inhibition. The Ki values of the M. oleifera extract against S. schenckii catalase (SsCAT) was found to be 0.7 μg/mL for MOE-AK and 0.08 μg/mL for MOE-ML. Catalase’s 3D structure in SsCAT is unknown. The homology of SsCAT was modeled with an in silico study using a 3D structure from SWISS MODEL and validation the predicted 3D structure was carried out using PROCHECK and MolProbity. Docking simulations were used to analyze protein interactions using Pymol, PoseView, and PLIP. The results revealed that M. oleifera glucosinolates interacts with SsCAT. A molecular interaction analysis revealed two inhibitor compounds (glucosinalbin and glucomoringin) with high binding affinity to key allosteric-site residues. The binding energies revealed that glucosinalbin and glucomoringin bind with high affinity to SsCAT (docking energy values: −9.8 and −9.0 kcal/mol, respectively). The findings of this study suggest that glucosinolates derived from M. oleifera could be used instead of synthetic fungicides to control S. schenckii infections. We hope that the findings of this work will be valuable for developing and testing novel natural anti-sporothrix therapeutic agents in the future.","PeriodicalId":21601,"journal":{"name":"Scientia Pharmaceutica","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45231971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ethanolic Extract of Ocimum sanctum Linn. Inhibits Cell Migration of Human Lung Adenocarcinoma Cells (A549) by Downregulation of Integrin αvβ3, α5β1, and VEGF","authors":"Ulayatul Kustiati, S. Ergün, S. Karnati, D. Nugrahaningsih, D. L. Kusindarta, H. Wihadmadyatami","doi":"10.3390/scipharm90040069","DOIUrl":"https://doi.org/10.3390/scipharm90040069","url":null,"abstract":"Adenocarcinoma lung cancer is a type of non-small cell lung carcinoma (NSCLC), which accounts for 85% of lung cancer incidence globally. The therapies that are being applied, both conventional therapies and antibody-based treatments, are still found to have side effects. Several previous studies have demonstrated the ability of the ethanolic extract of Ocimum sanctum Linn. (EEOS) as an ethnomedicine with anti-tumor properties. The aim of this study was to determine the effect of Ocimum sanctum Linn. ethanolic extract in inhibiting the proliferation, angiogenesis, and migration of A549 cells (NSCLC). The adhesion as well as the migration assay was performed. Furthermore, enzyme-linked immunosorbent assay (ELISA) was used to measure the expression of αvβ3 integrins, α5β1 integrins, and VEGF. The cells were divided into the following treatment groups: control (non-treated/NT), positive control (AP3/inhibitor β3 80 µg/mL), cisplatin (9 µg/mL), and EEOS at concentrations of 50, 70, 100, and 200 µg/mL. The results showed that EEOS inhibits the adhesion ability and migration of A549 cells, with an optimal concentration of 200 µg/mL. ELISA testing showed that the group of A549 cells given EEOS 200 µg/mL presented a decrease in the optimal expression of integrin α5β1, integrin αvβ3, and VEGF.","PeriodicalId":21601,"journal":{"name":"Scientia Pharmaceutica","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45661447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fabrication of Hydroxypropyl Methylcellulose Orodispersible Film Loaded Mirtazapine Using a Syringe Extrusion 3D Printer","authors":"Tanpong Chaiwarit, Niphattha Aodsab, Pimonnart Promyos, P. Panraksa, S. Udomsom, Pensak Jantrawut","doi":"10.3390/scipharm90040068","DOIUrl":"https://doi.org/10.3390/scipharm90040068","url":null,"abstract":"Depression is a mental illness causing a continuous negative feeling and loss of interest and affects physical and mental health. Mirtazapine (MTZ) is an effective medicine for treating depression, but patients lack compliance. However, transforming a pharmaceutical dosage form to an orodispersible film (ODF) could resolve this issue. This study aims to fabricate ODF-loading mirtazapine, using a syringe extrusion 3D printer, and compare its properties with the solvent-casting method. The ODFs were prepared by dissolving the mirtazapine in a hydroxypropyl methylcellulose E15 solution, and then fabricated by a 3D printer or casting. The 3D printing was accurate and precise in fabricating the ODFs. The SEM micrographs showed that the mirtazapine-printed ODF (3D-MTZ) was porous, with crystals of mirtazapine on the film’s surface. The 3D-MTZ exhibited better mechanical properties than the mirtazapine-casted ODF (C-MTZ), due to the 3D-printing process. The disintegration time of the 3D-MTZ in a simulated salivary fluid, pH 6.8 at 37 °C, was 24.38 s, which is faster than the C-MTZ (46.75 s). The in vitro dissolution study, in 0.1 N HCl at 37 °C, found the 3D-MTZ quickly released the drug by more than 80% in 5 min. This study manifested that 3D-printing technology can potentially be applied for the fabrication of ODF-containing mirtazapine.","PeriodicalId":21601,"journal":{"name":"Scientia Pharmaceutica","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44718638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modification of Taxifolin Properties by Spray Drying","authors":"A. Taldaev, R. Terekhov, I. Selivanova, Denis I. Pankov, M. Anurova, I. Markovina, Zhaoqing Cong, Siqi Ma, Zhengqi Dong, Feifei Yang, Y. Liao","doi":"10.3390/scipharm90040067","DOIUrl":"https://doi.org/10.3390/scipharm90040067","url":null,"abstract":"Taxifolin is known as an active pharmaceutical ingredient (API) and food supplement due to its high antioxidant activity, multiple pharmacological effects, and good safety profile. Previously, taxifolin spheres (TS) were obtained from industrially produced API taxifolin in Russia (RT). In our work, we perform a pharmaceutical analysis of this new taxifolin material versus RT. TS is an amorphous material; however, it is stable without the polymer carrier, as confirmed by Fourier transform infrared spectroscopy. Both RT and TS demonstrate high safety profiles and are assigned to Class 1 of the Biopharmaceutical Classification System based on the results of experiments with MDCK cells. The water solubility of the new taxifolin form was 2.225 times higher compared with RT. Hausner ratios for RT and TS were 1.421 and 1.219, respectively, while Carr indices were 29.63% and 19.00%, respectively. Additionally, TS demonstrated sustained release from tablets compared with RT: the half-life values of tablets were 14.56 min and 20.63 min for RT and TS, respectively. Thus, TS may be a promising object for developing oral antiseptics in the form of orally dispersed tablets with sustained release patterns because of its anti-inflammatory, -protozoal, and -viral activities.","PeriodicalId":21601,"journal":{"name":"Scientia Pharmaceutica","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43313784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Concepts for a New Rapid and Simple HPLC Method for Simultaneous Determination of Metoprolol and Meldonium in Pharmaceutical Dosage Forms","authors":"M. Piponski, M. Horyn, Kristina Grncaroska, O. Oleshchuk, E. Petrovska, Stefan Angelevski, T. Uglyar, T. Kucher, L. Logoyda","doi":"10.3390/scipharm90040065","DOIUrl":"https://doi.org/10.3390/scipharm90040065","url":null,"abstract":"Simultaneous determination of the tandem of drugs, like meldonium and metoprolol, with enormous polarity differences between them, requires thorough research and careful selection of chromatographic conditions. The three different CN-cyano groups with link-based particle columns, LiChrospher CN, Waters Spherisorb CNRP, Zorbax CN SB stationary phases, were tested, in an isocratic elution system, with a running mobile phase containing various concepts of composition contents. They were first with buffering salts which included acetonitrile and ammonium phosphate in one group, and then without buffering salts but with diluted acids, composed of acetonitrile and diluted acids as the second group. We can conclude that the most optimal concepts, in terms of expressiveness and environmental friendliness, were concepts using of column Zorbax CN SB (4.6 mm i.d.× 250 mm, 5 μm) and mobile phase ACN—0.15% NH4H2PO4 (50:50 and 60:40, v/v). There are very poor available data about ideas and usable information about the development of methods for simultaneous determination of these two active substances with polarity differences between them. We suggest that our work offered detailed and successful solutions for the mentioned aim using less sophisticated equipment for quality control and a lab for routine manufacturing control.","PeriodicalId":21601,"journal":{"name":"Scientia Pharmaceutica","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48406960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}